The overall goal of this Program Project is to identify the most potent biomarkers involved in the pathogenesis and progression of human breast cancer. This molecular fingerprint derived from an individual patient's tissue or tumor specimen would help clinicians distinguish women at highest risk for acquiring breast cancer, as well as those with breast cancer most in need of specific systemic therapies. Additionally, identification of these biomarkers should provide new targets for innovative therapeutic or treatment strategies. Building on accomplishments of the current Program Project, proposed individual projects will study: 91) integration of new and existing prognostic factor information into useful indexes to identify more accurately breast cancer patients at lowest and highest risk of recurrence, and to help predict responsiveness to specific therapies; (2) the role of estrogen receptor variants, many of them discovered here, as well as altered receptor expression, in progression of premalignant lesions and breast disease toward invasive cancer 94) a new gene on chromosome 14q apparently required for metastasis; and (5) the mechanism for the failed nuclear translocation of the BRCA1 protein which we have recently discovered. These projects will be supported by the San Antonio Breast tumor Bank and Data Network, containing many thousands of breast tumor specimens with associated clinical data and long-term follow-up, and also by core laboratories for histology/immunohistochemistry, tissue culture, and microdissection, along with an administrative core function. These highly interactive projects are designed to enhance our knowledge of how breast cells become malignant and invasive, and to use this knowledge to predict tumor behavior and probable treatment responses for the patient's benefit.